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Hormones of Adrenal gland, Hypothalamus, Pituitary Hormones
Mechanism of Action
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Hormones with cell surface receptors
- cAMP - 2nd messenger
Step 1
R - Receptor
PM - Plasma Membrane
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AC - Adenylyl Cyclase
GPCR - G Protein-Coupled Receptor
H binds to GPCR on PM
G-proteins
GTP binding regulatory protein
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Trimeric protein - 3 subunits - a, ß, ?
Step 2
Activation of G protein to Adenylyl cyclase
GDP - a - protein (inactive) + GTP ? a - GTP + ß? (active) G protein
Molecular switch
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Hormone & passed through signal passed
Signal Transduction
ATP ? Adenylyl cyclase (active in PM)
Hormones with intracellular receptors
Intracellular receptor, e.g., steroid hormone & Thyroid hormone
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Diffuse through PM
HR complex in cytoplasm & nucleus
HRE - Hormone Response Element
ATP ? cAMP (2nd messenger)
Phosphodiesterase
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5'-AMP
Cyclic AMP dependent protein kinase
Protein Kinase (PKA)
Tetrameric molecule
2 Regulatory + 2 Catalytic subunits (R2C2)
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cAMP ? R2C2 subunits due to act
ATP ? cAMP
Protein kinase (inactive) ? Protein Kinase (R2C2) (active)
Transfers PO4 group from ATP to diff enzyme protein
Phosphorylation usually takes place at the OH group of Serine, Threonine, or Tyrosine
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Activated / Inactivated
Covalent Modification
Hormones with cell surface receptors
2nd messenger mechanisms
- Important regulator of cell function
- Muscle contraction
- Cell division
- Gene regulation
- Secretion of hormones & neurotransmitters
- Nerve impulse conduction
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Rapid & transient rise in cytosolic Ca by opening of Ca channels in PM or ER
Intracellular Ca concentration gradient more than extracellular Ca
Ca transporting ATPase transporters accumulates Ca within the lumen of ER (sarcoplasmic reticulum) in muscle
Hormones increase cytosolic Ca by mechanism
Calmodulin ? confirmation change
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Ca dependent
Regulatory protein
4 Ca binding
Regulates various kinases
Ex: Myosin light chain kinase
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Ca dependent protein kinase
Hormones with cell surface receptors
PIP2 cascade
Hormones + Receptor (ex-serotonin) (PM)
HR complex
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G protein may activate PL-C-major player
PIP2 ? 1,4,5-IP3 + DAG
Membrane lipids
Smooth ER
Opens Ca resources
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Ca from intracellular stores (sarcoplasmic reticulum)
Muscle contraction
Glycogen breakdown
Exocytosis
PIP2 ? PLC ? DAG ? PKC
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IP3 ? Opens Ca channel ? Ca
Mechanism of Action of Steroid Hormones
Hormones with Intracellular Receptors
Ex: Steroid hormones + Nuclear receptor
Thyroid hormone
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Diffuse through PM
HR complex (cytoplasm)
Translocated to nucleus
HR binds to DNA sequences wind to specific hormones
Hormone Response Element
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Steroid Response Element on DNA Element
Enhancer
Transcription
mRNA
Translation
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Protein or Enzymes or Hormones
Ex: synthesis of amino transferases by Glucocorticoids
Synthesis of Ca binding protein by calcitonin
Abnormal G-protein signalling
Cholera
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Cholera toxin - the inside bacterium Vibrio cholerae
Enterotoxin
2 subunits
A subunit
B subunit
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Enters mucosal PM
Binds to ganglioside GM1
G protein irreversible activation
G alpha active
AC - continuously active
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cAMP prevents absorption of salts from intestine leading to watery diarrhoea
H2O loss from body
Loss of NaCl ? fatal results
Insulin
Protein hormone - 2 polypeptide chains
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Structure of Insulin
B chain - 30 AA
A chain - 21 AA
Biosynthesis of Insulin
(Pancreas)
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ß cells of Islets of Langerhans ? Preproinsulin precursor
Preproinsulin ? Proinsulin
Golgi apparatus ? Cleaved by proteinases
Connecting peptide removed
No. of AA in C peptide vary a/c species
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Mechanism of Action of Insulin
Insulin + Receptor on target cells (liver, muscle)
Insulin Receptor: Glycoprotein
4 subunits
2 a units
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2 ß subunits
Extracellular side to which insulin binds
Tyrosine kinase activity
Receptor Tyrosine kinase
Density, no. of receptors & larger tissue less sensitive to Insulin (Diabetes Mellitus Type II)
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Kinase activity
Tyrosine residues phosphorylated
Cellular response
Insulin + a subunit
2 units oligomeric
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ß receptors
Tyrosine kinase activity
Transmits signal to cytoplasm
Phosphorylated sites act as docking site for Insulin Response Substrate
IRS1 & IRS 2
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Recruits GLUT 4 to cell surface
Glycogen syntheses
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